Untitled

Benoit Petit-Demouliere . Franck Chenu .Michel Bourin
Forced swimming test in mice: a review of antidepressant activity
Received: 11 June 2004 / Accepted: 21 September 2004 / Published online: 18 November 2004
forced swimming test (FST) remains one of the most used
tools for screening antidepressants. Objective: This paper
reviews some of the main aspects of the FST in mice. Most
of the sensitivity and variability factors that were assessed
summarized data found in the literature of antidepressant
effects on the FST in mice. From this data set, we have
extrapolated information on baseline levels of strain, and
sensitivity against antidepressants.
shown that many parameters have to be considered in this
test to gain good reliability. Moreover, there was afundamental inter-strain difference of response in the
FST. Conclusions: The FST is a good screening tool withgood reliability and predictive validity. Strain is one of the
Half a century ago, antidepressants were discovered by
most important parameters to consider. Swiss and NMRI
serendipity. In 1954, it was observed that some treatments
mice can be used to discriminate the mechanisms of action
for tuberculosis were exerting a beneficial effect in the
of drugs. CD-1 seems to be the most useful strain for
sense of well-being (Selikoff and Robitzek ; Bloch et
screening purposes, but this needs to be confirmed with
al. ). These results set iproniazid as the first
some spontaneous locomotor activity studies.
antidepressant (Loomer et al. and the first memberof the monoamine oxidase inhibitor (MAO-I) family
Keywords Forced swimming test . Depression . Mouse .
(Zeller and Barsky At the same time, imipramine
was found to be effective in treating depression (Kuhn; Klerman and Cole ). At this point, a completely
new approach was exposed: the monoamine theory ofdepression or biogenic amine hypothesis (Bunney and
role of monoamines is not discussed here but it does not
Antidepressants with an atypical activity
fully describe the pathogenesis and aetiology of depres-
sion (Heninger et al. Hyman and Nestler ;Nestler ; Nestler et al.
Electronic Supplementary Material Supplementary material is
In addition to clinical research, pre-clinical studies were
necessary to test new drugs provided by pharmaceutical
industry. Depression is defined clinically as a pathologicalcomplex of psychological, neuroendocrine and somatic
B. Petit-Demouliere . F. Chenu . M. Bourin (*)
EA 3256 “Neurobiologie de l’anxiété et de la dépression”,
symptoms that cannot be reproduced in animals and
especially in mice. Only specific measurable behaviours
(endophenotypes) can be assayed to be relevant in human
depression (Holmes During this 50-year period,
numerous animal models of depression have been
designed, tested and assessed (Willner ; Lucki
it is difficult to determine this validity in animal models of
Mombereau The reserpine effects reversal test,
depression (Geyer and Markou ; Willner and Mitchell
designed by Costa et al. (), was the first attempt to
screen imipramine-like drugs and led to the isolation of
As semantic issues seem to exist between some authors
desipramine and the demonstration of its antidepressant
(Geyer and Markou Willner and Mitchell ), it is
effect. To date, few models are commonly used for
fundamental to have a clear definition of used terms. For
screening antidepressant effects or studying the mechan-
example, predictive validity and construct validity have
isms of action of these molecules. The aim of this paper is
not the same meaning for Willner and Mitchell than for
mainly to review the characteristics of one of these
Geyer and Markou. Predictive validity for Willner and
models: the forced swimming test (FST) in mice, and to
Mitchell is assessed by whether a model correctly
discuss the main parameters that influence the sensitivity,
identifies antidepressant treatments without making errors
specificity and reliability of this model.
of omission or commission, and whether potency in the
Porsolt et al. described “a new behavioural
model correlates with clinical potency. For Geyer and
method for inducing a depressed state in mice”. The idea
Markou, an animal model has predictive validity to the
arose out of some learning experiments they were doing
extent that it allows one to make predictions about
with rats in a water maze. Most rats were finding the exit
phenomena based on the performance of the model. The
within 10 min but they noticed that other rats ceased
narrow sense to refer to the ability of the model to identify
struggling altogether and remained floating passively
drugs with potential therapeutic value in humans appears
(Porsolt et al. ). To describe this new behavioural
limited for Geyer and Markou. It does not include the
model in mice, the following procedure was adopted “1 h
identification of any variables that influence both the
after a single i.p. injection mice were dropped into the
experimental preparation and the modelled phenomenon
cylinder (height 25 cm, diameter 10 cm, 6 cm of water at
in similar ways. This wider definition includes much of
21–23°C) and left for 6 min. Because little immobility is
what Willner and Mitchell would discuss under the rubric
observed during first 2 min, only that occurring during the
“construct validity”. Bearing in mind this opposition,
last 4 min was counted. The duration of immobility
predictive value in our paper will accord to the definition
occurring in each minute was scored. A mouse was judged
to be immobile when it ceased struggling and remained
Construct validity does not represent the same concept
floating motionless in the water making only movements
for these authors. Geyer and Markou defined it as the
necessary to keep its head above water” (Porsolt et al.
accuracy with which the test measures that which it is
Male CD (Charles River) mice of 20–25 g, were
intended to measure. For Willner and Mitchell, it is a
housed ten to a cage with free access to food and water.
means of bringing the theoretical accounts of both the
In the same paper, Porsolt tested a large range of
disorder itself and the disordered behaviour exhibited by
antidepressants and showed a reduction of immobility of
the model into alignment. It includes neurobiological
mice with all of them. The other usual clinical therapies
mechanisms, aetiology or psychosocial mechanisms. We
were also effective (e.g. electroconvulsive shock or
will use this definition of construct validity that includes
selective deprivation of REM sleep) (Porsolt et al. ,
etiological validity previously evocated (Geyer and
The goal of the present paper is to summarize the
Reliability refers to the consistency and stability with
advantages and drawbacks of the FST in mice, as well as
which the variables of interest are observed, and is
the factors of variability of the test through an extensive
relevant to both independent and dependant variables
Willner used a third parameter to describe some animal
models of depression: face validity (Willner ).
Face validity for an animal model of depression,
represents the analogy between the model and the disease
To evaluate the validity of an animal model, many criteria
(i.e. how well they apparently resemble the human
have to be explored. For example, we could consider
depressive state). It refers to the phenomenological
reliability and different types of validity: predictive, face,
similarity between the behaviour exhibited by the animal
construct, etiological, concurrent and discriminant. Un-
model and the specific symptoms of the human condition.
doubtedly, the more types of validity a model satisfies, the
This criterion is often criticized because of its non-
greater is its value, utility and relevance to the human
scientific aspect. It sums up specific patterns of depression
condition. To establish the value of a model in basic
and the model should not show features that are not seen
neurobiological research, few of these parameters have to
clinically. Although it appears to be useful to validate
be satisfied (Geyer and Markou It was argued that
models, such a criterion is actually not necessary (Geyer
there are only two criteria that a model must satisfy to
and Markou Because the pharmacotherapy of
establish its value in basic neurobiological research:
depression typically requires chronic drug treatment to
reliability and predictive validity. Nevertheless, the pro-
obtain a full response, face validity (Willner takes
cess of construct validation is valuable in further devel-
account of the necessity, or not, to use chronic adminis-
opment and refinement of the model; however, in practice
tration to have an antidepressant effect and the specificity
of observed features. Irrespective to how it responds to
24 days were effective at 10 mg/kg per day and 18 mg/kg
acute antidepressant treatment, to have face validity, an
per day administered in drinking water. This delay of
animal model if depression must respond to chronic
action provides further data to increase the face validity of
FST in mice, even if their experimental paradigm was not
These types of validity are discussed below for the FST.
the original method for the FST. (Dulawa et al.
For other types of validity, the FST was estimated to have
Moreover, we have to consider that some authors using
a lack of convergent validity and a possible etiological
standard methods showed that fluoxetine was effective
acutely at 16 mg/kg in the FST with CD mice (Da-Rochaet al. This shows the preponderant place ofmethodological parameters in behavioural studies (e.g.
In addition, from an ethical point of view, this animal
The FST is currently a popular model, due to the low cost
experiment requires only a single exposure to the stressful
of the experiments and because it is arguably the most
stimulus (Thierry et al. ). The used dose in the test as
reliable model available (Holmes Moreover, it has
well as in other tests in mice are high doses compared to
been reported to be reliable across laboratories (Borsini
human but the pharmacokinetic parameters in mice are
very different (i.e. half-life is about 1 h for mice comparedto several hours in human). Face validity for the FST withmice is not strong; chronic administration remains to be
fully studied in order to increase this face validity.
To evaluate predictive validity, correlating potenciesbetween a model and the condition it models is possible
(Willner In a comparative review of drug effects onimmobility time in mice, Borsini and Meli adopted a limit
The construct validity of the FST is difficult to establish
of 20% reduction of immobility to consider an antide-
and questionable. Indeed, the onset of immobility
pressant effective on the test. They show that 94% of
observed during the test is hard to interpret. Porsolt et
antidepressants decrease the immobility time in mice
al. () described this state as a behavioural despair
(Borsini and Meli In this study, they found that
“reflecting a state of lowered mood”. He had also
83% of classes of drugs decrease immobility time in the
dissociated hypothermia induced by forced swimming
mouse. This lack of specificity may be largely explained
from immobility occurring in these conditions and also
by methodological considerations. Some authors changed
from drug-induced hypothermia in rats (Porsolt et al.
the scoring method, other authors recorded animal move-
). The anthropomorphic interpretation was assessed
ments by using automated devices. Moreover, false
and replaced by other assumptions: a shift from active
positive effect of motor activity enhancing drugs would
coping to passivity, a means to conserve energy (Arai et al.
have been detected with an actimeter, where psychostim-
ulant drugs could reduce immobility without antidepres-
“entrapment” described in clinical situations (Cryan and
sant effect (Porsolt et al. Nevertheless, the FST is a
Mombereau ). This passive behaviour could also be
suitable model to detect antidepressants due to the fact that
considered as unwillingness to maintain effort in this
it detects the majority of antidepressants and discriminates
inescapable situation. Immobility may be seen as an
antidepressants from neuroleptics and anxiolytics (Borsini
adaptative response to an inescapable situation. This
strategy could be perceived as a successful coping rather
Together, these data provide us with a broad spectrum
of antidepressant effects with good reliability and some
Immobility observed in the swim test seems not to be
answers to the lack of specificity of the test, which has
related to behaviour in the tests used in anxiety models
been discussed (Schechter and Chance ).
(elevated-plus maze, hole-board test, locomotor activity)(Hilakivi et al. ). Even if the onset of immobilityremains hard to interpret, the aetiological part of construct
validity could be highly relevant. The stress leading to thebehavioural despair may be involved in the aetiology of
A second characteristic of the FST is that acute drug
some types of depression in humans (Geyer and Markou
treatments are effective in this model and do not
). Nevertheless, the FST has a very little construct
correspond to the clinical time course of their action.
validity due to this acute and non-ecologically relevant
One of the main arguments increasing the face validity is
stressor that produces this behaviour (Willner and Mitchell
that chronic treatments reinforce the effects of antidepres-
sants on immobility. It showed several differences between
To summarize, FST has strong predictive validity, good
chronic and subchronic treatment of a SSRI, fluoxetine, in
reliability, some face validity and poor construct validity.
the FST with BALB/c mice weighting 25–35 g (Dulawa et
In a review of the causes of immobility in the FST, West
al. ). Four days of treatment were ineffective, whereas
) concluded that FST “no longer appears to be a
valid model of depression. Nonetheless the forced swim
factor that could potentially be used in the treatment of
test is still likely to be useful in understanding anti-
depression. They used the FST and showed that brain-
depressants treatments”. This point of view should be
derived neurotrophic factor (BDNF) infusion in the ventral
moderated by a consideration on “what is a valid model of
tegmenta area resulted in 57% shorter latency to immo-
bility relative to control animals, in the FST in rats (Eisch
When pre-clinical tests were created to study the
et al. ). This use of the FST had already been
depressive state, the first role for models of depression
described previously with a 70% decrease in the immo-
was to predict antidepressant potency. Moreover, the
bility time compared to vehicle-infused controls after
validity of these tests was largely based on an empirical
BDNF infusion (Siuciak et al. ). Other ways of
observation, namely that the two major groups of
investigation for depression use the FST as model of
antidepressants, MAO-I and tricyclic drugs (TCAs), are
depression. Acute antidepressant treatment attenuates
swim stress-induced corticosterone release in the rat
The FST, as described by Porsolt et al. (), has been
(Baez and Volosin ). NK2-receptor antagonists, K+
designed to be “a primary screening test for antidepres-
channel openers and K+ channel blockers were considered
sants”. For this purpose, FST is a good model for
for their antidepressant-like properties in the forced swim
screening antidepressants, maybe the best one. FST
test (Guo et al. ; Redrobe et al. ; Slattery et al.
shows a strong sensitivity to monoamine alterations, but
). Nitric oxide synthase (NOS) or neurosteroids have
it should not be forgotten that other antidepressants
been tested in the FST with mice to look for an
treatments, such electroconvulsive shock, are efficient
antidepressant-like effect (Harkin et al. Khisti et
(Porsolt et al. ). To summarize these ideas, we can
al. Many studies keep using the FST, not only for
consider that “The FST models a very specific cluster of
screening for antidepressant effects, but for a more
stress-induced behaviours that have no direct, empirical
neuropsychological purpose. This utilization of the FST
relation to depression symptoms in humans, but which are
differ from the monoaminergic purpose it is often used.
nonetheless exquisitely sensitive to monoaminergic ma-
Nevertheless, this model of depression is not only linked
nipulations” (Holmes Additional possibilities for
to monoamine. The uncontrollable stress involved during
the FST should be considered on a more neuropharmaco-
the test may implicate many mechanisms of reaction that
logical point of view. This test also provides a useful
could be considered as possible investigation ways. The
model to study neurobiological and genetic mechanisms
fact that electroconvulsive seizures are effective in the test
underlying stress and antidepressant responses (Porsolt
argues for its ability to pick up broader mechanisms of
action (Nestler et al. The relevance of using the
Moreover, new approaches of research for antidepres-
FST for this new ways of research needs clinical
sant treatments continue to use the FST as a preliminary
correlations to validate also the FST for this utilization.
test. For example, some authors work on neurotrophic
The development of clinically effective antidepressant
Table 1 Summary of some modifications tested on the FST in mice
Bourin et al. (1998a); David et al. (2001a)
Alonso et al. (1991); David et al. (2001b); Voikar et al. (2001)
Hilakivi et al. (1989); Yates et al. (1991)
Lucki et al. (2001); Voikar et al. (2001); Bai et al. (2001); David et al. (2003)
Arai et al. (2000); Taltavull et al. (2003)
drugs with novel mechanisms should give answers to this
parameter provide a way to distinguish the antidepressant
drugs from caffeine, anticholinergics, and antihistaminics,
Another point is the utilization of the FST for
which gave a false positive response in 10 cm diameter
genetically modified animals that is applicable to study
cylinders. The selective effect of antidepressants, namely,
mechanisms of action of antidepressant on the test. For
the rotatory locomotor activity during swimming can also
example, the decrease of immobility observed after
be studied (Sunal et al. In our laboratory, we use a
paroxetine administration in wild-type mice is absent in
cylinder with the closest available diameter to the original
5-HT1B knockout in the test (Gardier et al. ). Other
test’s diameter, associated with a check of variation of
data with knock-out mice can be useful to determine the
locomotor activity that can discriminate false-positive
role of NA or 5-HT in the test; for example with mice
lacking serotonin transporter (Holmes et al. ordopamine-beta-hydroxylase deficient mice (Cryan et al.
Depth of water This parameter had to be considered as
This new employment of the test permits to better
mice should not sense a limit under the level of water.
know the mechanisms of action of drugs on the FST
Their tails should not touch the bottom of the cylinder or
involving or not the monoamine, i.e. for new possible
the behaviour of the mice would be altered. Increased
therapies for example, BDNF+/– mice (MacQueen et al.
depth of water decreases the time spent immobile. No
or inducible BNDF knock-out (Monteggia et al.
paper clearly described this process in mice; this parameter
was shown to alter the behaviour of the rat (Borsini andMeli Detke and Lucki The originaldescription of the FST by Porsolt et al. () explains
that 6 cm of water is sufficient. But mice can sense thebottom of the cylinder with this level of water. In our
There have been many modifications of the FST but
laboratory, the water level is at least 10 cm. Some
improvements of the test are often poorly validated
modifications of Porsolt’s paradigm have often been used;
(Bourin et al. ). Many parameters have been assessed
one of the most quoted is the method of Aley and Kulkarni
in order to increase the sensitivity, specificity and
). They measure immobility in a glass jar (21×12
reliability of detection of antidepressant activity. The
cm) containing 12 cm of water maintained at 22±1°C,
following list describes some of these modifications of
during a 6-min period. It is important to consider that the
FST (Table The two columns of Table separate each
only main modification of the original test is the increased
modification between variability and sensitivity. A “vari-
depth of water. This procedure is consistent with the one
ability factor” is assessed to check what parameter could
we use and should be considered as the actual standard
increase or decrease reliability of the test between different
Interval of observation/scoring Porsolt’s paradigm hasbeen modified by some researchers in order to increase the
sensitivity or the specificity of the FST. Some authors havecreated a totally new analysis procedure for scoring
Automated device/water waves Different procedures have
immobility. The observation interval can be separated into
been elaborated to automate the FST. Video-tracking,
5-s parts in which the main behaviour is scored (Lucki
computer analysis or wave analysis were used to score the
). Analysis of the behaviour of the mice can be totally
immobility of rodents. From the data set, one can extract
different with categorization of a specific behaviour
full or partial turns, clockwise or counter-clockwise
(Schramm et al. Some authors made a series of
rotations, total activity, and speed of swimming clockwise
observations at 30 s. intervals and the mouse was rated as
and counter-clockwise (Denenberg et al. Another
immobile (score 0) or not (score 1) for each observation
author used an apparatus consisting of a transparent plastic
cylinder (10×20 cm) containing 7 cm of water (23°C).Movement by the animal created a waveform in the water,
Time between treatment and FST This factor is not often
resulting in a converted digital signal (Browne ). The
considered but may explain some of the differences
ease of use of these systems appears not to counterbalance
between FST results. Two possibilities seem to be
the cost of the equipment. Few studies use an automated
available: acute injection 1 h before the FST as described
video-tracking device, and mainly as a confirmation tool
by Porsolt et al. or acute injection then the FST
(Eisch et al. Nevertheless, some automated devices
when the maximal effect is intended. This requires a time-
employed in FST studies were reported to be reliable for
antidepressant screening (Yoshikawa et al.
Water temperature The influence of water temperature on
Cylinder diameter To test this parameter, mice were forced
immobility time of the mice was studied. An effect of
to swim for 15 min in tanks of 10 (the original diameter of
water temperature was revealed; a higher temperature
the Porsolt’s forced swimming chamber), 20, 30, and 50
(35°C) resulted in shorter immobility time after 10 min of
cm diameter in 20 cm deep water. Modifications of this
forced swimming (Arai et al. Other data suggest
that immobility, which develops rapidly during forced
Environment of the laboratory Interactions with laboratory
swimming in cold water, may result from dramatic
environment have been studied in several strains of mice
inhibition of neural functions because of severe brain
on few behavioural tests (open field, elevated plus maze,
hypothermia (Taltavull et al. Currently, most
water maze, alcohol preference) (Crabbe et al.
studies use warmer water between 23°C and 28°C. In
Despite standardization, there were systematic differences
our laboratory, we choose a temperature between 23°C and
in behaviour across three different laboratories. In our
opinion, FST is less sensitive to variation of laboratoryenvironment (noise, air temperature, light, atmosphere
Wheel water tank Some authors have tried to measure
immobility time in another way. A wheel was immersed inthe water tank. Mice placed on this apparatus keep turning
Food restriction Food restriction can strongly modify
the wheel vigorously; when they abandon their attempts to
behavioural responses, as shown with amphetamine or the
escape from the water, the wheel stops turning. The
FST. The authors used FST for two sessions with two
number of rotations of the water wheel is counted. All
groups of DBA/2 mice. One group was isolated and food
antidepressants tested increased the number of rotations as
restricted, the other group was isolated but had free access
tranquillizers, anticholinergics and antihistaminics were
to food. Immobility time was significantly decreased in the
not effective. It was suggested that this water wheel test
food-restricted group compared to the other group (Cabib
was more appropriate as screening test for antidepressants
than Porsolt’s test with regard to both objectivity andspecificity (Nomura et al. ).
Gender Differences of sensitivity between male andfemale mice were revealed by some studies dependingon the strain used. David et al. ) described a
different sensitivity to antidepressants in the FST related togender. Imipramine and paroxetine were active on CD1
Acute versus chronic administration The effectiveness of
male and female but at different doses. Another study
acute treatment is a particularity of the FST. Useful for a
showed a difference between male and female mice but
screening test, it appears to decrease the face validity of
only in some strains; FVB females, for example, had a
this model, as the clinical time course requires chronic
shorter floating time than males (Voikar et al.
administration to be active. Experiments were made to
Sexual differences have also been described in another
find out the effects of chronic administration on the FST.
study of immobility, which was higher in males than in
Subchronic or acute effects were increased by chronic
Housing of animals/isolation of animals All studies have
Age of the mice This parameter should be considered in
shown that housing was a critical parameter. In the above
parallel with weight. Our team has already shown a strong
mentioned study of Cabib (see food restriction section), a
difference between younger and older mice groups.
group of DBA/2 mice was isolated for 13 days and
Sensitivity to some antidepressants is profoundly altered.
compared with group-housed mice in the FST. They
Tricyclic, noradrenaline reuptake inhibitors (NRI) and
showed a significant increase of the immobility time in the
serotonin reuptake inhibitors were more active in 4-week-
isolated group (Cabib et al. Yates et al.
old mice than 40-week-old Swiss mice (Bourin et al.
linked this difference with the age of the mice. After
David et al. In our laboratory experiments, we
having isolated mice for 24 h prior to a 15-min FST, they
showed an increase in immobility time in 17- to 21-day-old Swiss Webster mice but not in 26- to 30-day-old mice.
Circadian rhythm An effect of circadian rhythm was
In another study, the immobility time in the FST was
shown in response to antidepressants in the FST. FST was
shortened in NIH Swiss mice isolated for 2 or 5 days,
carried with three strains of mice: C3H, C57BL/6J and
suggesting an improved ability to cope with stressful
ND/4. Immobility time was scored at noon (1200–1400
situations (Hilakivi et al. Yates et al. Isolation
hours) and midnight (0000–0200 hours). For C3H/Hen
seems to have strain-dependent effects on the FST, but
mice, duration of immobility was greater at midnight
none of these studies had the same isolation time. If
(Dubocovich et al. Another study did not show any
isolated for a longer period (8 weeks), mice displayed
difference between the FST made at noon (1100–1200
lower levels of immobility time when exposed to this test
hours), early dark (2000–2100 hours) and at midnight
(Karolewicz and Paul ). Nevertheless, isolation, e.g.
(0100–0200 hours) for BALB/c and C57BL/6J mice
for surgery, had to be specified in methods of a paper, as it
(Raghavendra et al. ). Genetics studies on the Clock
may modify dramatically immobility time of the FST.
gene, implicated in circadian rhythm, revealed an effect ofthis parameter on immobility time (Easton et al.
Observer The most important source of variability (and the
Studies in our laboratory are only made between 0800 and
best way to consider in order to increase the sensitivity of
1200 hours to avoid any risk of behavioural modification
the FST), with identical environmental parameters, is the
observation. Like all behavioural studies, the observer is
the main actor of the test and reproducibility between
second session. This second session has been assessed for
laboratories is a matter that affects all these tests. The
the construct validity of the FST. Memory process was
scoring of the immobility time should be strongly
involved to explain immobility of the rat. The absence of
considered and assessed by all teams. The mouse is
second session with mice removes this problem and
judged to be immobile when it makes only movements
simplifies the test. In their experiments, Alcaro et al.
necessary to keep its head above water. It can move in the
) evaluated behavioural responses to FST in naive
cylinder but without struggling movements. The analysis
animals and in animals pre-exposed to the FST 14 days
of active behaviours in the FST has strengthened the
before the test session. They showed a major effect of the
possibility of replicating the experiments.
pre-session FST in mice on immobility time with adramatic increase after pre-exposure. For Andreatini and
Side preference in rotation A study was made on side
Bacellar (), “this test showed a very low intra-class
rotational preference of mice during the FST. Krahe et al.
correlation coefficient in the test-retest design, which
concluded that side preferences of spontaneous
suggests a poor reliability of these measures”. These
rotational behaviour may account for inter-individual
results suggest that the behavioural parameters of the
behavioural despair are not stable. Therefore, they arepossibly more related to state than trait characteristics, this
Strains Strain is one of the most important parameters to
test is not appropriate to evaluate trait characteristics
deal with (Lucki et al. ). Important differences exist
which are supposed to be stable over time without
between strains in both immobility observed and effects of
treatment. Some authors use the test/retest paradigm to
imipramine (Porsolt et al. ). Genetic background
avoid variations and to maintain consistency in the
could modify response by providing an inappropriate
immobility time between different groups (Hirani et al.
baseline level of behaviour (Holmes There is a
maximal tenfold difference in baseline immobility scoresin control animals between strains and baseline level doesnot correlate with antidepressant sensitivity (Lucki et al.
Several gender dissociations suggest the strain andtask specificity (Voikar et al. Intra-strain and inter-
Many antidepressants have been tested with the FST on
strain comparisons indicate that the biological substrates
mice. Some results available for all classes of antidepres-
mediating performance in the FST and the tail suspension
sants with different strains of mice are reviewed here.
test (TST) are not identical. For example, in NIH-Swiss
In the literature, the lowest control immobility time was
mice, a 7-fold difference in baseline immobility was
obtained with FVB/NJ (13 s) mice and highest with ddY
observed between the FST and TST. By contrast, the
baseline immobility in C57BL/6 mice was similar in both
Table summarises the results for three inbred strains
procedures (Bai et al. ). There is a continuum of
and four outbred strains that are compared over their
variation in basal responses from almost no time spent
results in the FST. A more detailed version of this table,
immobile by DBA/2J mice to more than 210 s of
with more antidepressants and strains, is available as
immobility in a 360-s test session with Balb/cJ mice
Electronic Supplementary Material (ESM).
(O’Neil and Moore In one of our studies, we have
Inbred strains have been found very defective in the
shown that drug sensitivity is genotype dependent. FST
FST with antidepressants. Only one type of antidepressant
results have shown that Swiss mice were the most
(DRI), bupropion, was significantly effective in the FST
sensitive strain to detect serotonin (5-HT) and/or norad-
with C57BL/6Rj. For C57BL6j and DBA/2, no positive
renaline (NA) treatment. The use of DBA/2 inbred mice
result coupled with a locomotor test was found in papers
may be limited, as an absence of antidepressant-like
we analysed. Outbred strains of mice are more responsive
response was observed in the FST (David et al.
to antidepressants in the FST than inbred strains. These
Control mice from the same breeders with comparable
four outbred strains may be used for at least three classes
housing conditions should have the same immobility time
of treatments. The most frequently used strains, CD1,
in all laboratories. However, a gene-environment interac-
NMRI and Swiss, have positive results with most of the
tion is possible and may account for some difference
antidepressants in the FST. HaM/ICR seems to be very
between laboratories (Wahlsten et al. ). For example,
responsive to drugs in the FST but it is a rare strain. Only
in our data set, animals of the same strain that received no
one paper was found to use this strain on the FST (De
treatments do not have the same immobility time (for CD-
Graaf et al. There are many differences between
1 from 135 s to 223 s of immobility time).
strains; DBA/2, for example, does not have an appropriateresponse to the FST. This strain should not be used for
Test/retest This method is used normally for rats. In a first
behavioural studies with the FST. CD-1 is not useful to
session, the animal is able to discover the test, rat usually
discriminate different mechanisms of action in the test. It
explore the water surface and dive. In a second session
could be used as a screening model but, to recommend this
were they will be scored, rats are familiarized to the test
strain, we need to know if Dopamine Reuptake Inhibitors
and do not try to dive. Mice do not have this behaviour
(DRI, e.g. bupropion), NRI and MAO-I are effective in the
and this explain the easy use of mice that do not need a
Table 2 Antidepressant effects on the FST with different strains of
relation to depression symptoms in humans” (Holmes
). Care must be taken on the strain used for the test
and all the experimental parameters involved. For ascreening test, CD-1 can be a good strain to use to find out
if a treatment has an antidepressant-like activity.
Despite their intrinsic limitations, the full potential of
animal models of depression has not yet been realized and
they represent an under-explored opportunity for drug
development. Such opportunities arise from the molecular
dissection of the biological features of the models (Wongand Licinio ).
*, treatment is effective and locomotor activity was tested without
Anjaneyulu et al. Biziere et al. (Biziere et
+, treatment is effective but locomotor activity was not tested
−, treatment has no potency and does not increase locomotor activity al. Bourin et al. (), Bourin et al.
Different categories of drugs are listed in the first column. For
Clenet et al. Cryan et al. (Devoize et al.
example, DRI includes bupropion, nomifensine or amineptine.
), Devoize et al. Eschalier et al. (), Kato
Atypical antidepressants include mianserin, iprindole and others. A
positive result, represented by a star, signifies that at least one studyshowed a significant effect of one drug of the considered category.
Miura et al. Mogilnicka et al. Redrobe et
For a more detailed table, Electronic Supplementary Material is
al. (), Rogoz et al. (), Scotto di Tella and Mercier
available with all drugs and effects reported in different studies
), Stenger et al. (), Szymczyk and Zebrowska-Lupina Zocchi et al. ).
FST with CD-1 without increasing spontaneous locomotoractivity of the animals.
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